Osteoporosis, sarcopenia and changes in fat distribution with age increase risk of fractures, affect quality of life, and are of major public health significance. Investigations into the genetic architecture of endophenotypes of these conditions could lead to better prediction of who is at greatest risk as well as revealing targets for therapies to delay disease onset or diminish their effects on afflicted individuals. Covariation among these conditions may be due to pleiotropy, although little is known about the specific genes involved. I explored relationships among twenty-two measures of arm and leg bone mineral density and geometry, arm and leg lean mass and arm and leg fat mass using data from two populations of Afro-Caribbeans from the island of Tobago: a sample of 1,937 unrelated men aged ≥ 40 years and a set of 470 men and women aged ≥ 18 years in seven extended pedigrees (mean family size = 67). I also performed genomewide association (GWA) studies of lumber spine and femoral neck bone mineral density (BMD) and fractures in an older (aged ≥ 70 years) population of European and African Americans (n = 1,663 and 1,139 respectively). Hierarchical and principal component (PC) analysis revealed three clusters: (1) a “geometry group” that comprises mostly bone geometry traits and lean mass (PC1); (2) a “density group” that comprises mostly BMD traits (PC2); and (3) a “fat mass group” that comprises measures of fat mass (PC3). Estimates of residual heritability ranged from 0.206 to 0.763 (p < 0.007 for all traits). Linkage analysis revealed significant evidence (LOD > 3.3) for quantitative trait loci (QTLs) on two chromosomes: 10q for PC1 and tibial periosteal circumference and 21q for PC3 and arm fat mass. GWA analyses of BMD and fractures in European and African Americans revealed several dozen potential candidate loci with suggestive levels of significance (p ≤ 5 × 10⁻⁶), the most promising of which is SLC4A7 on 3p24.1, a sodium bicarbonate cotransporter expressed in osteoclasts. Thus, I present evidence for specific QTLs with pleiotropic effects on multiple body composition traits, as well as loci associated with areal BMD and fracture risk. Additional analyses of these regions could reveal genes that jointly influence susceptibility to osteoporosis, sarcopenia and obesity.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-06072011-110049 |
| Date | 22 September 2011 |
| Creators | Minster, Ryan Lee |
| Contributors | M. Michael Barmada, Candace M. Kammerer, Joseph M. Zmuda, Robert E. Ferrell, Daniel E. Weeks |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-06072011-110049/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0057 seconds